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Arbovirus Infections As Screening Tools for the Identification of Viral Immunomodulators and Host Antiviral Factors

Arbovirus Infections As Screening Tools for the Identification of Viral Immunomodulators and Host Antiviral Factors

Published on: September 13, 2018

Astrovirus replication is dependent on induction of double-membrane vesicles through a PI3K-dependent,

Theresa Bub^1,2, Virginia Hargest¹, Shaoyuan Tan¹

¹Department of Infectious Diseases, St. Jude Children's Research Hospital , Memphis, Tennessee, USA.

Journal of Virology

|September 5, 2023

Abstract:

Human astrovirus is a positive-sense, single-stranded RNA virus. Astrovirus infection causes gastrointestinal symptoms and can lead to encephalitis in immunocompromised patients. Positive-strand RNA viruses typically utilize host intracellular membranes to form replication organelles, which are potential antiviral targets. Many of these replication organelles are double-membrane vesicles (DMVs). Here, we show that astrovirus infection leads to an increase in DMV formation through a replication-dependent mechanism that requires some early components of the autophagy machinery. Results indicate that the upstream class III phosphatidylinositol 3-kinase (PI3K) complex, but not LC3 conjugation machinery, is utilized in DMV formation. Both chemical and genetic inhibition of the PI3K complex lead to significant reduction in DMVs, as well as viral replication. Elucidating the role of autophagy machinery in DMV formation during astrovirus infection reveals a potential target for therapeutic intervention for immunocompromised patients. IMPORTANCE These studies provide critical new evidence that astrovirus replication requires formation of double-membrane vesicles, which utilize class III phosphatidylinositol 3-kinase (PI3K), but not LC3 conjugation autophagy machinery, for biogenesis. These results are consistent with replication mechanisms for other positive-sense RNA viruses suggesting that targeting PI3K could be a promising therapeutic option for not only astrovirus, but other positive-sense RNA virus infections.

Insights

Human astrovirus replication depends on double-membrane vesicles (DMVs) that utilize the class III phosphatidylinositol 3-kinase (PI3K) complex. Targeting PI3K offers a potential therapeutic strategy for astrovirus and other positive-sense RNA virus infections.

Area of Science:

Virology
Cell Biology
Immunology

Background:

Human astrovirus is a positive-sense RNA virus causing gastrointestinal illness and encephalitis in immunocompromised individuals.
Positive-strand RNA viruses often use host cell membranes to create replication organelles, frequently double-membrane vesicles (DMVs), which are potential antiviral targets.

Purpose of the Study:

To investigate the role of intracellular membranes, specifically DMVs, in astrovirus replication.
To identify host factors, particularly components of the autophagy machinery, involved in DMV formation during astrovirus infection.
To explore the therapeutic potential of targeting these host factors for astrovirus infection.

Main Methods:

Studied DMV formation in astrovirus-infected cells.
Investigated the involvement of autophagy machinery components, including the class III phosphatidylinositol 3-kinase (PI3K) complex and LC3 conjugation.
Utilized chemical and genetic inhibition of the PI3K complex to assess its impact on DMV formation and viral replication.

Main Results:

Astrovirus infection induces DMV formation in a replication-dependent manner.
Early autophagy components, specifically the class III PI3K complex, are required for DMV biogenesis.
LC3 conjugation machinery is not essential for DMV formation in astrovirus infection.
Inhibition of the PI3K complex significantly reduces both DMV formation and viral replication.

Conclusions:

Astrovirus replication necessitates the formation of DMVs, leveraging the class III PI3K complex but not LC3 conjugation.
These findings align with replication strategies of other positive-sense RNA viruses.
Targeting the PI3K pathway presents a promising therapeutic avenue for astrovirus and potentially other positive-sense RNA virus infections, especially in immunocompromised patients.

Read full analysis

Keywords:

astrovirus autophagy class III PI3K double-membrane vesicle replication organelle

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